C-X-C chemokine receptor type 4 (CXCR4) is a class A rhodopsin-like seven-transmembrane G-protein coupled receptor. CXCR4 is activated by CXCL12 resulting in various signaling pathways including chemotaxis, cell survival and proliferation, intracellular calcium flux, and gene transcription. The endogenous chemokine binds CXCR4 via a “two site” mechanism, CRS1 and CRS2. A variety of small molecule CXCR4 antagonists bind the CRS2 pocket and inhibit signal propagation. Our group has extensive experience developing CXCR4 antagonists based upon the lead compound TIQ-15, resulting in the identification of several clinical candidates. Although a crystal structure of small molecule and cyclic peptide antagonists bound to CXCR4 has been elucidated, these compounds differ significantly from our scaffold. Therefore, we aimed to provide insights into future compound development through binding mode elucidation of our lead candidates via computational methods. Initial induced-fit docking indicated lead molecules could plausibly bind CXCR4 within the CRS2 pocket in two similar but differing binding modes. To parse out which binding mode is indeed the most favorable, parallel binding pose metadynamics (BPMD) and 100ns molecular dynamic (MD) simulations were employed. Both the BPMD and MD simulations correlated quite well with one another and identified one pose more stably bound the receptor over the other. Additionally, the computational data was supplemented by an agreement in experimental SAR data trends from similar compounds within our pipeline and the identified binding mode. Altogether, the data strongly suggested one binding mode is favored and is likely how amino-heterocycle tetrahydroisoquinoline CXCR4 antagonists bind the receptor. Future work will entail the use of this information to identify future compound candidates for synthesis, examination of how different structural modifications affect signaling outcomes <i>in vitro</i>, and crystallization efforts of amino-heterocycle tetrahydroisoquinoline molecules bound to CXCR4.

Binding mode elucidation of amino-heterocycle tetrahydroisoquinoline CXCR4 antagonists: Applications and perspectives for drug discovery

ACS Spring 2022

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.